Manganese based macromolecular theranostic probes

Theranostic is a modern field of medicine that combines therapy methods with diagnostic methods. Therapeutic strategies such as chemotherapy, hyperthermia or radiation are used together with diagnostic methods such as Magnetic Resonance Imaging (MRI). In contrast to conventional contrast media (CM), which only enable non-specific staining of tissues and organs, a theranostic offers targeted diagnostic visualization and therapy. Theranostics with pronounced selectivity towards tumors can revolutionize the course of malignant diseases. As part of this research project, novel paramagnetic compounds for targeted drug delivery and visualization of malignant diseases using MRI will be developed. Paramagnetic complexes of salinomycin (SAL) and doxorubicin (DOX) will be produced and characterized for targeted tumor visualization by MRI. The potential properties as chelating agents, which at the same time have a high intrinsic antitumor activity compared to uncoordinated ligands or the free drugs will be evaluated. The main goal of the project is the validation and detailed characterization of innovative theranostics. The obtained results will be compared with those of other natural bio-polysaccharide ligands such as dextran and chitosan DTPA / DOTA derivatives and with clinically used CM. Manganese (Mn2+) will be coupled as a T1 enhancer for MRI. Thus, Mn2+ offers a good alternative to the recently discussed problems of accumulation and toxicity of the gadolinium (Gd) -based CM being routinely used in the clinic. As a final step, the produced paramagnetic complexes will be encapsulated into bacterial cells, so-called bacterial ghosts (BGs), serving as tumor-specific transport vehicles. This will enable a targeted transport and an increased tumor accumulation of the active compound. In addition, the development of new application and "targeting" strategies to avoid side effects and circumvent resistance development is a central aspect of modern cancer research. After successful synthesis and characterization of the novel theranostics, their magnetic susceptibility and cytotoxicity towards selected tumor cell lines will be determined and compared with clinically applied MRI-CM or drugs. The most promising candidates will be finally examined in vivo for tumor targeting and tumor uptake in a 9.4 Tesla MRI scanner. In summary, this project will investigate innovative chemical properties of antitumor antibiotics and modified biopolymers in order to develop novel theranostics. These novel Mn-based biomarkers with intrinsic antitumor activity represent an innovative and highly efficient All-in-One Theranostic for future (pre-) clinical applications by early diagnosis and optimization of the course of cancer therapy.

As part of this research project, new contrast agents for magnetic resonance imaging (MRI-CAs) were produced that also have a pronounced antitumor effect. This allows the use of these so-called theranostics - the combination of a therapeutic and a diagnostic agent in one - for simultaneous patient-friendly treatment and for monitoring the success of a chemotherapy. In addition, new MRI-CAs, which also enable early detection and targeted delivery to diseased tissue such as a tumor, represent one of the most important tasks for human health. In many cases, an MRI diagnosis is only made late and at an advanced stage of the disease. Currently used MRI-CAs are based mainly on the heavy metal gadolinium (Gd), which has provided valuable information for decades. However, recent concerns about toxicity and the enormous environmental impact of the released Gd are driving medical research towards the development of safer and more environmentally friendly MRI-CAs. Our project therefore also offers some safe alternatives to Gd such as contrast agents containing the endogenous elements manganese (Mn) or iron (Fe), or the non-metal fluorine (F). For the first time, salinomycin (Sal) - a natural antibiotic with extremely high anticancer activity - and doxorubicin, a clinically used anticancer agent, were successfully used as carrier molecules for Mn and Fe as alternative signaling agents in MRI to produce a powerful "all-in-one" theranostic tool for MRI. The new theranostics were characterized by various physicochemical methods and tested for their ability to eradicate cancer cells. To enable localized administration of the drug at low doses, selected highly potent compounds were loaded into empty bacterial "ghost cells" (BGs), which serve as intelligent, "cancer-seeking" transport particles. The anticancer effect was maintained and a strong signal was generated in MRI, proving the potential of the produced contrast agents as new alternative theranostics. Another group of innovative MRI-CAs developed in the project are superfluorinated biodegradable polymers containing F as a signaling element in MRI. These innovative formulations have already provided high-resolution MRI images and a not yet fully explored potential for precise and quantitative insights into the (patho)physiological status of many diseases. In addition, the produced biopolymer-based compounds represent a safe and precise diagnostic tool for vulnerable individuals who cannot be examined with the currently used clinical MRI-CAs, for example patients with impaired renal function. Various cancer-targeting molecules/transport vesicles as part of the new theranostics provide improved and specific localization in tumor tissue, enabling monitoring of cancer therapy and assessment of tumor stages. This breakthrough promises to pave the way for extensive clinical applications and facilitate broad implementation in routine medical practice. Furthermore, these innovative theranostics not only emphasize safety but also have a significantly lower ecological footprint compared to currently used Gd-based contrast agents.